Carnitine acetyltransferase is found in mammals but its in vivo role has not been definitively established. There is conjecture, however, that it allows acetyl carnitine to buffer the pool of acetyl-Coenzyme A and/or that it may be involved in intracellular transport of acetyl and other short chain acyl groups. Compounds which competitively bind to and thus inhibit carnitine acetyltransferase are useful to investigate the in vivo role of carnitine acetyltransferase and to verify or disprove the conjecture.
Fritz, I. B. and Schultz, S. K., "Carnitine Acetyltransferase II. Inhibition by Carnitine Analogues and by Sulfhydryl Reagents", J. Biol. Chem., 240, 2188-2192 (1965) investigate the carnitine acetyltransferase inhibiting power of various carnitine analogues and other compounds. They do this by using carnitine acetyltransferase to catalyze the reaction EQU Acetylcarnitine+Coenzyme A.revreaction.acetyl-Coenzyme A+carnitine
and measuring the velocity of reaction in the presence of the tested compounds and record results in terms of K.sub.i ' values where lower values indicate greater inhibiting power. The inhibitors uncovered by Fritz and Schultz are relatively weak and are subject to metabolism and thus are not suitable for the role investigation previously mentioned.
Carnitine palmitoyltransferase (CPT) has a recognized role in mammals in the following chain of reactions. Outside the mitochondria, it catalyzes the reaction EQU Long chain acyl-Coenzyme A+carnitine.revreaction.long chain acyl carnitine+Coenzyme A
The long chain acyl carnitine is carried by carnitine transporter from cytoplasm into the mitochondrial matrix. Inside the mitochondria CPT catalyzes the reaction EQU Long chain acyl carnitine+Coenzyme A.revreaction.long chain acyl-Coenzyme A+carnitine
Within the mitochondria, the long chain acyl-Coenzyme A is catabolized to carbon dioxide and in the case of diabetics to ketones leading to ketoacidosis.
It has been suggested by G. Tutwiler in Carnitine Biosynthesis, Metabolism and Functions, Academic Press, N.Y., pp. 171-173 (1980), that inhibiting the fatty acid catabolism may reverse such ketoacidosis. Compounds which competively bind to and thus inhibit CPT are useful to investigate whether interruption of fatty acid catabolism does reverse ketoacidosis and are useful in the treatment of diabetes and as a substitute or supplement for insulin.
Bromoacetyl-L-carnitine has been shown in vitro to have a potent effect against T. Brucei, the causitive agent of African trypanosomiases. See Gilbert, R. J., Klein, R. A., and Johnson, P., "Bromoacetyl-L-Carnitine: Biochemical and Antitrypanosomal Actions Against Trypanosoma Brucei Brucei", Biochem. Pharmacol. 32, No. 22, 3447-3451 (1983). The potential of bromoacetyl-L-carnitine is limited in vivo because of toxicity due to release of bromine and/or bromoacetate. A more stable analog would eliminate this toxic effect.